Anti-spasmodic compositions specific for treating spasm of the colon



United States Patent ANTI-SPASMODIC COMPOSITIONS SPECIFIC FOR TREATINGSPASM OF THE COLON John H. Biel, Milwaukee, Wis., assignor to LakesideLaboratories, Inc., a corporation of Wisconsin No Drawing. ApplicationApril 8, 1957 Serial No. 651,167

15 Claims. (Cl. 167-65) This invention relates to an ester of cyclicamino-alcohols and particularly to the benzilic acid ester of N-methyl-3-hydroxypiperidine, non-toxic methonium derivatives thereof, andpharmaceutical compositions of the same.

This application is a continuation-in-part of application Serial No.2l7,4l3, filed March 24, 1951 which in turn is a continuation-impart ofapplication Serial No. 180,295 filed August 18, 1950, now abandoned.

The reduction of smooth muscle spasm, whether of musculotropic orneurotropic origin, by atropine and by various synthetic compoundsrelated in structure to atropine or papaverine, is well known. Whilemany of these compounds will effectively abolish one or the other typeof spasm, they are not capable of relieving both types of muscle spasm.Furthermore, the action of the known compounds is usually accompanied byundesirable side effects such as dilation of the pupil of the eye,dryness of the mouth, large increase in rate of heart beat,hypertension, nausea, and vomiting.

Some esters of N-alkyl-4-piperidinol have been found to be activeanti-spasmodics or spasmolytics, but such esters have never been putinto use. It is well known that changes in the positions of certainsubstituents on the piperidine ring may produce profound differences inthe physiological activity and effects of such compounds, whichdifferences are not predictable. Thus, N-methyl-4-phenyl-4-propionoxypiperidine is a potent analgesic whereas thecorresponding N-methyl-2-phenyl-2-propionoxy-piperidine has only slightanagesic properties and beta4-methyl-piperidine-ethyl benzoate hasconsiderable anesthetic action while the 2 and 3-methyl derivatives haveno such action. Hence, it will be seen that shifting a group from the4-position of the piperidine ring may cause complete loss of activity.

It is, therefore. an object of the present invention to provide acompound for pharmaceutical purposes and having the effect of reducingeither involuntary muscle or nervous spasm.

Another object of the invention is to provide a compound having ananti-spasmodic effect in humans, which compound is long-lasting inaction and which will have only a few undesirable side reactions ofminor importance.

A further object of the invention is to provide a series of substitutedacetic acid esters of N-methyl-3-piperidinol having longer activity andside reactions both less in numher and of lower intensity than othercompounds now in use for reducing spasm of human muscle or nerves.

I have found that N-methyl-3-piperidyl benzilate of the formula in theform of non-toxic methonium salts is effective as an anti-spasmodic inboth musculotropic and 'n'eurotropic spasms and has long duration ofaction with fewer undesirable side effects than various otheranti-spasmodic; now used.

Surprisingly, N-methyl-3-piperidyl benzilate methonium compounds have aunique, highly selective antispasmodic action in the lower part of thegastro-intestinal tract, i.e., the colon. N-methyl-3-piperidyl benzilatemethyl bromide is the first spasmolytic product which has ever beenapproved by the Food and Drug Administration as an agent which isselective for colonic disorders.

Such unexpected activity in the colon is even more surprising becausethe next adjacent homolog N-ethyl-3- piperidyl benzilate, as the methylbromide, does not display activity in the colon but is a selective agentfor peptic ulcer in the stomach and duodenum because of its action insuppressing gastric secretion and motility in this area.

The N-methyl-3-piperidyl benzilate methyl bromide salt has beenestablished by thorough clinical investigations to be selective in thecolon. Thus, it has been found to restore normal tone and motility inulcerative colitis, irritable colon, mucous colitis, spastic colitis,diverticulitis, diverticuloses, and diarrhea following gastrointestinalsurgery, and rectospasm while relieving pain, cramp, bloating and spasmavoiding urinary retention, dry mouth and visual difiiculties.

N-methyl-3-piperidyl benzilate may be prepared by preparing a mixtureN-methyl of 3-chloro-piperidine and benzilic acid in isopropanol andrefluxing the mixture. After filtering and concentrating the reactionmixture in vacuo it is added to water, acidified and the unreacted acidremoved with ether. After neutralizing the aqueous layer, the product isextracted with ether and the solution dried. After removing the etherthe free base is obtained by vacuum distillation.

The methonium salts of N-methyl-3piperidyl benzilate are readily formedby contacting the free base with a methylating agent in the presence ofa suitable solvent such as an hydrous ether. The desired salt formsquickly and generally precipitates from solution. In this way, themethyl iodide, methyl bromide, methyl chloride and methyl sulfate saltsmay be formed. The methonium salts which may be formed have the formuladistillation in vacuo, the residue treated with dilute aqueoushydrochloric acid and the aqueous acid mixture exitracted repeatedlywith ether. The aqueous phase was separated, made 'strongly alkalinewith 20% aqueous sodium hydroxide and extracted with ether. The etherextracts" were dried with potassium carbonate and distilled; the productwas collected at 175176 C. (0.03 mm.), yield 11.5 g. (59%). Thehydrochloride salt analyzed as follows:

Analysis.Calcd. for C H ClNO Cl, 9.78-; N, 3.87. Found: Cl, 9.73; N,3.76.

The ester base of Example 1 was dissolved in. 75 cc. of isopropylalcohol and 3.4 g. (0.037 mole) methyl bromide added. The reactionmixture was allowed to stand at 30 C. for two days and the productisolated by filtration, yield, 13 g. (87%), MP. 228-229 C. dec.

Analysis.Calcd. for C H BrNO Br, 19.05; N, 3.34. Found: Br, 18.91;N,3.33.

The anti-spasmodic activity of methonium salts of N- methyI-B-piperidylbenzilate is about equal to atropine but is free of the side effectsnormally inherent with atropine therapy. The therapeutic dose ofmethonium salts of N-methyl-3-piperidyl benzilate is generally in therange of to 50 mgm. per dose and may be administered at intervalsthroughout the day as needed although four doses a day are usually foundto be highly satisfactory. The optimum dosage from all viewpointsappears to be 25 mgm. four times a day. Such dosages are of courseadministered orally, and preferably in tablet, capsule, or

some other convenient pharmaceutical form in conventional use. Standardcarriers like starch and sugar may be used as well as the ordinarylubricants, binders, and

disintegrating agents as are required to form tablets.

Various changes and modifications of the invention can be made and, tothe extent that such variations incorporate the spirit of thisinvention, they are intended to be included within the scope of theappended claims.

What is claimed is:

1. An anti-spasmodic pharmaceutical composition in unit dosage formadapted for human treatment without causing significant dryness of themouth and dilation of the eye pupil comprising a compound of the formulawherein Y is a non-toxic anion, and a pharmaceutical carrier.

2. A pharmaceutical composition in unit dosage form adapted for humananti-spasmodic treatment without causing significant dryness of themouth and dilation of the eye pupil comprising a member of the groupconsisting of N-methyl-3-piperidyl benzilate and compounds of theformula 1 ad p for-human pas diaucatmentwi hout sai s- 4 ing significantdryness of the mouth and dilation of the eye pupil comprisingN-methyl-3-piperidyl benzilate methyl bromide and a pharmaceuticalcarrier.

4. A pharmaceutical composition in unit dosage form 5 adapted for humananti-spasmodic treatment without caus ing significant dryness of themouth and dilation of the eye pupil comprising N-methyl-3-piperidylbenzilate methyl chloride and a pharmaceutical carrier.

5. An anti-spasmmodic pharmaceutical composition in unit dosage formadapted for human anti-spasmodic treatment without causing significantdryness of the mouth and dilation of the eye pupil comprisingN-methyl-3- piperidyl benzilate methyl iodide and a pharmaceuticalcarrier.

6. An anti-spasmodic pharmaceutical composition in unit dosage formadapted for human anti-spasmodic treatment without causing significantdryness of the mouth and dilation of the eye pupil comprisingN-methyl-3- piperidyl benzilate methyl sulfate and a pharmaceuticalcarrier.

7. The process which comprises administering a compond to a human forits therapeutic anti-spasmodic elfect, without casing significantdryness of the mouth and 'dilation of the eye pupil, said compound beingof the forwherein Y is a non-toxic anion.

8. The process which comprises administering N- methyl-3-piperidylbenzilate methyl bromide to a human for its therapeutic anti-spasmodiceffect, without causing significant dryness of the mouth and dilation ofthe eye pupil.

9. A member of the group consisting of N-methyl-3- piperidyl benzilateand compounds of the formula wherein Y is a nontoxic anion.

10. N-methyl-3-piperidyl benzilate l1. N-methyl- 3 -piperidyl benzilatemethyl halide, where the methyl halide is a member selected from thegroup consisting of methyl bromide, methyl chloride and methyl iodide.

12. N-methyl-3-piperidyl benzilate methyl chloride.

13. N-methyl-3-piperidyl benzilate methyl bromide.

14. N-methyl-3-piperidyl benzilate methyl iodide.

15. N-methyl-3-piperidyl benzilate methyl sulfate.

. References Cited in the file of this patent UNITED STATES PATENTSWolfes et al. Aug. 23, 1938 Feldkamp Dec. 5, 1950 OTHER REFERENCESBurtner et al.: J.A.C.S., vol. 65, pp. 262-267 (1943).

Grant: Hackhs Chem. Dictionary, 3rd ed., 1944, p. 594, McGraw-l-lill.

Blicke et al.: J .A.C.S., vol. 64, 1942, pp. 428-431.

McElvain et al.: J.A.C.S., vol 70, pp. 1826-28, January 1948.

Ford-Moore et al.: J. Chem. Soc. (London), 1947, pp.

U.S, Disp, 25th ed., 1955, pp. 1783-1790, Lippincott CO:

V f w UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTWN Patent No.2,918,408 December 22 1959 John H. Biel It is hereby certified thaterror appears in the-printed specification of the above numbered patentrequiring correction and thatthe said Letters Patent should read ascorrected below.

Column l, line 40, for "anagesic" read analgesic column 2, line 38 for"an hydrous" read anhydrous line 50, after "such" insert as column 4line 9 for "ant1- spasmlrnochic read anti-spasmodic line 23,; for"casing" read causing same column 4, line 50, after "benz1late insert aperiod.

(SEAL) Attest:

KARL H. AXLINE Attesting Officer ROBERT C. WATSON Commissioner ofPatents

1. AN ANTI-SPASMODIC PHARMACEUTICAL COMPOSITION IN UNIT DOSAGE FORMADAPTED FOR HUMAN TREATMENT WITHOUT CAUSING SIGNIFICANT DRYNESS OF THEMOUTH AND DILATION OF THE EYE PUPIL COMPRISING A COMPOUND OF THE FORMULA